Changes in the pulsatile secretion of gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) are critical for the regulation of events leading to ovulation, as well as to the inhibition of ovulation prior to puberty and during other physiological periods of infertility. Endogenous opioid peptides (EOPs) have been known for many years to suppress pulsatile secretion of GnRH and LH, specifically mediating the negative feedback influence of progesterone. Findings in the past grant period have provided evidence that one type of EOP system, the dynorphin system, plays a key role in the control of GnRH pulses. Specifically, we have identified three sub-populations of dynorphin neurons that contain progesterone receptors, in the preoptic area, anterior hypothalamus and arcuate nucleus of the hypothalamus, which are strong candidates for mediating the negative feedback influence of progesterone. Based on these findings, we now propose to determine which of these sub-populations (1) send direct projections to GnRH cells;and (2) mediate the negative feedback actions of progesterone. In addition, we recently discovered that orphanin FQ (OFQ), an EOP not previously known to play a role in reproduction, is co-localized in almost all GnRH neurons, including their fibers in the median eminence and have preliminary evidence that OFQ inhibits episodic LH secretion. Hence, we will also explore the role of OFQ in control of episodic LH and GnRH secretion. These questions will be explored using the sheep as an animal model because of advantages that include the similarity of its estrous cycle to the human menstrual cycle and the ability to directly monitor GnRH pulses without anesthesia. In addition, EOPs have been shown to play a major role in mediating progesterone negative feedback during the luteal phase in humans as well as sheep. Thus, these studies may lay the foundation for the development of better treatments for pathological disruptions of reproductive function, and the basis for the design of novel contraceptive techniques.